The Mechanism of Allosteric Coupling in Choline Kinase α1 Revealed by the Action of a Rationally Designed Inhibitor

Authors

  • María Sahún-Roncero,

    1. Institute of Biocomputation and Physics of Complex Systems (BIFI), University of Zaragoza, BIFI-IQFR (CSIC) Joint Unit, Mariano Esquillor s/n, Campus Rio Ebro, Edificio I+D; Fundacion ARAID, Edificio Pignatelli 36 (Spain)
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  • Dr. Belén Rubio-Ruiz,

    1. Departamento de Química Farmaceútica y Orgánica, Facultad de Farmacia, Universidad de Granada c/Campus de Cartuja s/n, Granada (Spain)
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  • Dr. Giorgio Saladino,

    1. Computational Biophysics group, Spanish National Cancer Research Center, Melchor Fernández Almagro, 3, Madrid (Spain)
    2. Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ (UK)
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  • Dr. Ana Conejo-García,

    1. Departamento de Química Farmaceútica y Orgánica, Facultad de Farmacia, Universidad de Granada c/Campus de Cartuja s/n, Granada (Spain)
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  • Prof. Antonio Espinosa,

    1. Departamento de Química Farmaceútica y Orgánica, Facultad de Farmacia, Universidad de Granada c/Campus de Cartuja s/n, Granada (Spain)
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  • Dr. Adrián Velázquez-Campoy,

    1. Institute of Biocomputation and Physics of Complex Systems (BIFI), University of Zaragoza, BIFI-IQFR (CSIC) Joint Unit, Mariano Esquillor s/n, Campus Rio Ebro, Edificio I+D; Fundacion ARAID, Edificio Pignatelli 36 (Spain)
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  • Dr. Francesco Luigi Gervasio,

    1. Computational Biophysics group, Spanish National Cancer Research Center, Melchor Fernández Almagro, 3, Madrid (Spain)
    2. Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ (UK)
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    • These authors contributed equally.

  • Prof. Antonio Entrena,

    1. Departamento de Química Farmaceútica y Orgánica, Facultad de Farmacia, Universidad de Granada c/Campus de Cartuja s/n, Granada (Spain)
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    • These authors contributed equally.

  • Dr. Ramon Hurtado-Guerrero

    Corresponding author
    1. Institute of Biocomputation and Physics of Complex Systems (BIFI), University of Zaragoza, BIFI-IQFR (CSIC) Joint Unit, Mariano Esquillor s/n, Campus Rio Ebro, Edificio I+D; Fundacion ARAID, Edificio Pignatelli 36 (Spain)
    • Institute of Biocomputation and Physics of Complex Systems (BIFI), University of Zaragoza, BIFI-IQFR (CSIC) Joint Unit, Mariano Esquillor s/n, Campus Rio Ebro, Edificio I+D; Fundacion ARAID, Edificio Pignatelli 36 (Spain)

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  • We thank the European Synchrotron Radiation Facility (ESRF) at Grenoble and the Diamond Light Source (DLS) at Oxford, specifically beamlines ID23-1 and I03, respectively. We thank the Fundación Agencia Aragonesa para la Investigación y el Desarrollo (ARAID, Spain), the Ministerio de Economía y Competitividad (MEC, Spain, grants BFU2010-19504, BFU2010-19451, SAF2009-11955, and BIO2010-20166), the Consejería de Innovación, Ciencia y Empresa of the Junta de Andalucía (grant P07-CTS-03210), the Ministerio de Educación for a FPU fellowship (AP2007-03115) to B.R.-R., and Diputación General de Aragón (Grupo Protein Targets, B89) and the Comunidad Autónoma de Madrid S2010-BMD-2457 (BIPEDD2). This work was granted access to the HPC resources of HECToR, within the Distributed European Computing Initiative (FP7/2007-2013, RI-283493).

Abstract

original image

Im Mittel doch symmetrisch: Kombinierte experimentelle und Computerstudien der Bindungsweise eines rational entworfenen Inhibitors der dimeren Cholinkinase α1 (CHOKα1) erklären die molekularen Mechanismen der negativen Kooperativität (siehe Schema) und wie die Monomere verknüpft sind. Die Ergebnisse geben Aufschluss darüber, wie die Symmetrie des Dimers trotz fehlender Konservierung in den statischen Kristallstrukturen teilweise konserviert werden kann.

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